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Abstract:

The present invention relates to methods and devices that help to curb
appetite and/or reduce food intake. In one embodiment, the methods and
devices of the present invention include a small intestinal/duodenal
insert comprising an elongated member with at least one flow reduction
element that can cause the stimulation of one or more biological signals
of satiety.

Claims:

1. A device adapted and configured for use within the duodenum of a
mammal, comprising: a spine having a length, a proximal end and a distal
end; a first atraumatic feature positioned adjacent to the spine proximal
end; a second atraumatic feature positioned adjacent to the spine distal
end wherein the length of the spine is selected so that when the first
atraumatic feature is in the stomach the second atraumatic feature is in
the fourth portion of the duodenum; and a flow reduction element
positioned along the spine and having a proximal end, a distal end, an
interior portion, an exterior portion, wherein at least a portion of the
device is at least partially made from or coated with a lipid-philic
material.

2. The device of claim 1 wherein the at least a portion of the device
that is at least partially made from or coated with a lipid-philic
material is the flow reduction element.

3. The device of claim 1 wherein the at least a portion of the device
that is at least partially made from or coated with a lipid-philic
material is the spine.

4. The device of claim 1, wherein the at least a portion of the device
that is at least partially made from or coated with a lipid-philic
material is configured to absorb and distribute temporally lipids from
passage ingesta.

5. The device of claim 4, wherein the at least a portion of the device
that is at least partially made from or coated with a lipid-philic
material is configured such that absorption and distribution temporally
of the lipids from passage ingestia increases hormonal regulation.

6. The device of claim 2, wherein the flow reduction element is
configured to hold lipids therein for a period of time.

7. The device of claim 2, wherein the flow reduction element is
configured such that a portion of the flow reduction element prevents
flow of chyme more than a second portion of the flow reduction element.

8. The device of claim 2, wherein the flow reduction element is a bulge
formed of lipid-philic material.

9. The device of claim 2, wherein the flow reduction element is at least
partially formed from the lipid-philic material.

10. The device of claim 9, wherein the flow reduction element is formed
completely of the lipid-philic material.

11. The device of claim 2, wherein at least a portion of the interior or
the exterior of the flow reduction element is at least partially coated
with the lipid-philic material.

12. The device of claim 11, wherein the flow reduction element is
entirely coated with the lipid-philic material.

13. The device of claim 3, wherein the spine is hollow.

14. The device of claim 1, further comprising a feature on the spine
positioned to restrict movement of the flow reduction element relative to
the spine.

15. The device of claim 1 wherein the at least a portion of the device
that is at least partially made from or coated with a lipid-philic
material is a structure within the flow reduction element.

16. The device of claim 15, wherein the structure within the flow
reduction element is attached to the flow reduction element.

17. The device of claim 15, wherein the structure within the flow
reduction element is attached to the spine.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent application Ser.
No. 13/420,457, filed Mar. 14, 2012, and titled "METHODS AND DEVICES TO
CURB APPETITE AND/OR REDUCE FOOD INTAKE," now Publication No.
US-2012-0172999-A1, which is a continuation of U.S. patent application
Ser. No. 11/300,283, filed Dec. 15, 2005, and titled "METHODS AND DEVICES
TO CURB APPETITE AND/OR REDUCE FOOD INTAKE," now U.S. Pat. No. 8,147,561,
which is a continuation-in-part of U.S. patent application Ser. No.
10/999,410, filed Nov. 30, 2004, and titled "METHOD AND APPARATUS FOR
REDUCING OBESITY," now U.S. Pat. No. 7,931,693, which claims priority to
U.S. Provisional Patent Application No. 60/547,630, filed Feb. 26, 2004
and titled "METHOD AND APPARATUS FOR REDUCING OBESITY." Each of these
patent applications are herein expressly incorporated by reference in
their entirety for all purposes.

INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same extent as
if each individual publication or patent application was specifically and
individually indicated to be incorporated by reference.

FIELD

[0003] The present invention relates to methods and devices that help to
curb appetite and/or to reduce food intake (hereinafter "reduce food
intake").

BACKGROUND

[0004] Obesity, defined as a body mass index (BMI) of greater than 30, is
a major health concern in the United States and other countries. Current
research suggests that one in three Americans and more than 300 million
people world-wide are obese. www.who.int/nut/obs.htm (last visited Dec.
13, 2005). Complications of obesity include many serious and
life-threatening diseases including hypertension, diabetes, coronary
artery disease, stroke, congestive heart failure, pulmonary
insufficiency, multiple orthopedic problems, various cancers and a
markedly decreased life expectancy. Intentional weight loss, however, can
improve many of these medical complications associated with obesity.

[0005] While weight loss can improve many of the medical complications
associated with obesity, its management as a health concern has proven
troublesome. A variety of approaches including dietary methods,
psychotherapy, behavior modification, and pharmacotherapy have failed to
control the rapid growth in the incidence and severity of obesity seen in
the United States. According to the Center for Disease Control, obesity
contributes to about 111,909 deaths annually, just behind tobacco
(435,000) and ahead of alcohol (85,000), car accidents (43,000) and guns
(29,000). Mokdad et al., 291(10), JAMA 1238-1245 (2004); Flegal et al.,
293(15) JAMA 1861-1867 (2005). Further, the estimated annual cost of
obesity in the U.S. in 2000 was about $117 billion. Centers for Disease
Control and Prevention available at
http:/www.cdc.gov/nccdphp/aag/aag_dnpa.html (last visited Nov. 11, 2005).

[0006] The severity of problems associated with obesity has led to the
development of several drastic surgical procedures. One such procedure
physically reduces the size of the stomach so that a person cannot
consume as much food as was previously possible. These stomach reduction
surgeries had limited early success, but now it is known that the stomach
can restretch over time, limiting the achievement of sustained weight
loss in many individuals. Another drastic surgical procedure induces the
malabsorption of food by reducing the absorptive surface of the
gastrointestinal (GI) tract, generally via by-passing portions of the
small intestine. This gastric by-pass procedure further has been combined
with stomach reduction surgery. While these described surgical procedures
can be effective to induce a reduction in food intake and/or overall
weight loss in some, the surgical procedures are highly invasive and
cause undue pain and discomfort. Further, the described procedures may
result in numerous life-threatening postoperative complications. These
surgical procedures are also expensive, difficult to reverse, and place a
large burden on the national health care system.

[0007] Non-surgical approaches for the treatment of obesity also have been
developed. For example, one non-surgical endoscopic approach to treating
obesity includes the placement of a gastric balloon within the stomach.
The gastric balloon fills a portion of the stomach, providing the patient
with a feeling of fullness, thereby reducing food intake. Many problems
are associated with the gastric balloon device, however, including poor
patient tolerance and complications due to rupture and/or migration of
the balloon. Further, sham-controlled studies have failed to show that
implantation of a gastric balloon produces a better reduction in food
intake than dieting alone. Trostler et al., 19(7) Int. J. Obes. Relat.
Metab. Disord. 489-495 (1995); Geliebter et al. 15(4) Int J Obes. 259-266
(1991); Mathus-Vliegen et al., 99(2) Gastroenterol. 362-369 (1990);
Lindor et al., 62(11) Mayo Clin. Proc. 992-996 (1987).

[0008] Other non-surgical devices designed to induce weight loss limit the
absorption of nutrients in the small intestine by funneling food from the
stomach into a tube found within the small intestine so that the food is
not fully digested or absorbed within the small intestine. While this
type of device may be somewhat effective at limiting the absorption of
consumed food, there is still room for a variety of improvements in
non-surgical devices designed to induce weight loss and/or a reduction in
food intake.

[0009] An understanding of biological events that contribute to the
creation of satiety signals provides an opportunity to develop "smart"
nonsurgical devices that can trigger such events. The amount of food that
individuals consume is largely dependent on biological signals between
the gut and the brain. Specifically, hormonal signals from the gut to the
brain are correlated with both the onset and cessation of food intake.
While increased levels of hormones such as ghrelin, motilin and
agouti-related peptide are involved in the promotion of appetite and the
onset of food intake, increased levels of a number of other hormones are
involved in the cessation of food intake.

[0010] Various biologic events contribute to the physiologic cessation of
food intake. Generally, as a meal is consumed, the ingested food and
by-products of digestion interact with an array of receptors along the GI
tract to create satiety signals. Satiety signals communicate to the brain
that an adequate amount of food has been consumed and that an organism
should stop eating. Specifically, GI tract chemoreceptors respond to,
without limitation, products of digestion (such as sugars, fatty acids,
amino acids and peptides) while stretch and mechanoreceptors in the
stomach and proximal small intestine respond to, without limitation, the
physical presence of consumed foods. Chemoreceptors respond to the
products of digestion by, without limitation, causing the release of
hormones or other molecular signals. These released hormones and/or other
molecular signals can stimulate nerve fibers to send satiety signals to
the brain. The arrival of these signals in the brain can trigger a
variety of neural pathways that can reduce food intake. The released
hormones and/or other molecular signals can also travel to the brain
themselves to help create signals of satiety. Stretch and
mechanoreceptors generally send satiety signals to the brain through,
without limitation, stimulation of nerve fibers in the periphery that
signal the brain. The present invention provides methods and devices that
help to reduce food intake by providing non-surgical devices that trigger
the aforementioned biological events that contribute to the creation of
satiety signals.

SUMMARY OF THE DISCLOSURE

[0011] The present invention provides methods and devices to reduce food
intake by one or more of: (i) slowing the passage of food so that food
remains in the GI tract for a longer period of time and thereby triggers
satiety signals for a longer period of time; (ii) stimulating stretch and
mechanoreceptors within the GI tract to send satiety signals to the brain
to decrease the likelihood or amount of food intake; and/or (iii)
stimulating chemoreceptors within the GI tract to send satiety signals to
the brain to decrease the likelihood or amount of food intake.

[0012] In one embodiment the present invention includes a duodenal/small
intestinal insert comprising an elongated member wherein the elongated
member has a proximal end and a distal end; an anchoring member engaged
with the proximal end of the elongated member; and at least one flow
reduction element on the elongated member wherein when the anchoring
member is anchored the at least one flow reduction element is in the
small intestine of the organism and wherein when the duodenal/small
intestinal insert is placed within an organism in this manner, the insert
triggers an initial physiological effect that contributes to the creation
of one or more biological signals of satiety.

[0013] Another device of the present invention includes a duodenal/small
intestinal insert comprising an elongated member with at least one angle
and at least one flow reduction element wherein the at least one angle
matches an angle in the small intestine of an organism and wherein the at
least one flow reduction element has a diameter that matches the diameter
of the small intestine of the organism and wherein the at least one angle
and the at least one flow reduction element allow the duodenal/small
intestinal insert to lodge in the small intestine of the organism such
that it remains in the small intestine for a period of time. In one
embodiment of this device of the present invention, the insert triggers
an initial physiological effect that contributes to the creation of one
or more biological signals of satiety.

[0014] In another embodiment of the devices of the present invention, the
triggering of the initial physiological effect is caused by the slowing
of the passage of consumed food through the GI tract of the organism. In
another embodiment of the devices of the present invention, the diameter
of the at least one flow reduction element is sized to restrict but not
occlude the movement of consumed foods through the small intestine. In
another embodiment of the devices of the present invention, the diameter
of the at least one flow reduction element is about 1 cm. In another
embodiment of the devices of the present invention, the diameter of the
at least one flow reduction element is about 2 cm. In another embodiment
of the devices of the present invention, the diameter of the at least one
flow reduction element is about 3 cm.

[0017] In another embodiment of the devices of the present invention the
triggering of the initial physiological effect that contributes to the
creation of one or more biological satiety signals is caused by contract
and/or pressure exerted on the wall of the small intestine by the
duodenal/small intestinal insert.

[0018] In another embodiment of the devices of the present invention the
initial triggering occurs through activation of at least one
chemoreceptor. In another embodiment of the devices of the present
invention the initial triggering occurs through the activation of at
least one stretch receptor. In another embodiment of the devices of the
present invention the initial triggering occurs through the activation of
at least one mechanoreceptor.

[0019] In another embodiment of the devices of the present invention the
one or more biological signals of satiety is transmitted at least in part
through stimulation of afferent nerve fibers. In another embodiment of
the devices of the present invention the afferent nerve fibers are vagal
afferent nerve fibers.

[0020] In another embodiment of the devices of the present invention the
one or more biological signals of satiety is transmitted at least in part
by molecules released as a result of stimulation of the chemoreceptor. In
another embodiment of the devices of the present invention the molecules
are hormones. In another embodiment of the devices of the present
invention the molecules are selected from one or more of the group
consisting of cholecystokinin, peptide YY3-36, glucagon-like peptide
1, gastric-inhibitory peptide, neurotensin, amylin, leptin, bombesin,
calcitonin, calcitonin gene-related peptide, somatostatin, neuromedin U
and glucagon.

[0021] In another embodiment of the devices of the present invention the
molecules activate a receptor in the periphery to cause a subsequent
physiological effect. In another embodiment of the devices of the present
invention the molecules activate a receptor in the liver to cause a
subsequent physiological effect. In another embodiment of the devices of
the present invention the molecules activate a receptor in the pylorus to
cause a subsequent physiological effect. In another embodiment of the
devices of the present invention the molecules activate a receptor in the
stomach to cause a subsequent physiological effect. In another embodiment
of the devices of the present invention the molecules travel to the brain
to activate a receptor to cause a subsequent physiological effect.

[0022] In another embodiment of the devices of the present invention, the
elongated member further comprises at least one angle that matches an
angle of said organism's small intestine. In another embodiment of the
devices of the present invention the elongated member further comprises
an angle of about 70°. In another embodiment of the devices of the
present invention the elongated member further comprises an angle of
about 71°. In another embodiment of the devices of the present
invention the elongated member further comprises an angle of about
72°. In another embodiment of the devices of the present invention
the elongated member further comprises an angle of about 73°. In
another embodiment of the devices of the present invention the elongated
member further comprises an angle of about 74°. In another
embodiment of the devices of the present invention the elongated member
further comprises an angle of about 75°. In another embodiment of
the devices of the present invention the elongated member further
comprises an angle of about 76°. In another embodiment of the
devices of the present invention the elongated member further comprises
an angle of about 77°. In another embodiment of the devices of the
present invention the elongated member further comprises an angle of
about 78°. In another embodiment of the devices of the present
invention the elongated member further comprises an angle of about
79°. In another embodiment of the devices of the present invention
the elongated member further comprises an angle of about 80°. In
another embodiment of the devices of the present invention the elongated
member further comprises an angle of about 81°. In another
embodiment of the devices of the present invention the elongated member
further comprises an angle of about 82°. In another embodiment of
the devices of the present invention the elongated member further
comprises an angle of about 83°. In another embodiment of the
devices of the present invention the elongated member further comprises
an angle of about 84°. In another embodiment of the devices of the
present invention the elongated member further comprises an angle of
about 85°. In another embodiment of the devices of the present
invention the elongated member further comprises an angle of about
86°. In another embodiment of the devices of the present invention
the elongated member further comprises an angle of about 87°. In
another embodiment of the devices of the present invention the elongated
member further comprises an angle of about 88°. In another
embodiment of the devices of the present invention the elongated member
further comprises an angle of about 89°. In another embodiment of
the devices of the present invention the elongated member further
comprises an angle of about 90°. In another embodiment of the
devices of the present invention, the elongated member comprises two
angles, each matching an angle of said organism's small intestine.

[0023] The present invention also includes methods. In one embodiment the
methods of the present invention include placing a duodenal/small
intestinal insert in the small intestine of an organism wherein the
duodenal/small intestinal insert comprises an elongated member with at
least one angle and at least one flow reduction element wherein the at
least one angle matches an angle in the small intestine of an organism
and wherein the at least one flow reduction element has a diameter that
is less than the diameter of the small intestine of the organism and
wherein the at least one angle and the at least one flow reduction
element allow the duodenal/small intestinal insert to lodge in the small
intestine of the organism such that it remains in the small intestine for
a period of time. In one embodiment of this method of the present
invention the duodenal/small intestinal insert triggers an initial
physiological effect that contributes to the creation of one or more
biological signals of satiety. In another embodiment of the methods of
the present invention, the diameter is sized to restrict but not occlude
the movement of digested food through the small intestine. In another
embodiment of the methods of the present invention, the diameter is about
1 cm. In another embodiment of the methods of the present invention, the
diameter is about 2 cm. In another embodiment of the methods of the
present invention, the diameter is about 3 cm.

[0024] Another embodiment of the methods of the present invention include
a method for reducing food intake wherein the method comprises
positioning a duodenal/small intestinal insert in an organism wherein the
insert comprises an elongated member with a proximal end and a distal
end; an anchoring member engaged with the proximal end of the elongated
member; and at least one flow reduction element on the elongated member
wherein when the anchoring member is anchored the at least one flow
reduction element is in the small intestine of the organism, and when the
insert is so placed, the duodenal/small intestinal insert triggers an
initial physiological effect that contributes to the creation of one or
more biological signals of satiety.

[0025] In another embodiment of the methods of the present invention, the
triggering of the initial physiological effect is caused by the slowing
of the passage of consumed food through the small intestine of the
organism.

[0028] In another embodiment of the methods of the present invention, the
triggering of the initial physiological effect that contributes to the
creation of one or more biological signals of satiety is caused by
contact and/or pressure exerted on the wall of the small intestine of the
organism by the duodenal/small intestinal insert.

[0029] In another embodiment of the methods of the present invention, the
triggering of the initial physiological effect occurs through the
activation of at least one chemoreceptor. In another embodiment of the
methods of the present invention, the triggering of the initial
physiological effect occurs through the activation of at least one
stretch receptor. In another embodiment of the methods of the present
invention, the triggering of the initial physiological effect occurs
through the activation of at least one mechanoreceptor.

[0030] In another embodiment of the methods of the present invention, the
one or more biological signals of satiety is transmitted at least in part
through stimulation of afferent nerve fibers. In another embodiment of
the methods of the present invention, the afferent nerve fibers are vagal
afferent nerve fibers.

[0031] In another embodiment of the methods of the present invention, the
one or more biological signals of satiety is transmitted at least in part
by molecules released as a result of stimulation of a chemoreceptor. In
another embodiment of the methods of the present invention, the molecules
are hormones. In another embodiment of the methods of the present
invention, the molecules are selected from one or more of the group
consisting of cholecystokinin, peptide YY3-36, glucagon-like peptide
1, gastric-inhibitory peptide, neurotensin, amylin, leptin, bombesin,
calcitonin, calcitonin gene-related peptide, somatostatin, neuromedin U
and glucagon.

[0032] In another embodiment of the methods of the present invention, the
molecules activate a receptor in the periphery to cause a subsequent
physiological effect. In another embodiment of the methods of the present
invention, the molecules activate a receptor in the liver to cause a
subsequent physiological effect. In another embodiment of the methods of
the present invention, the molecules activate a receptor in the pylorus
to cause a subsequent physiological effect. In another embodiment of the
methods of the present invention, the molecules activate a receptor in
the brain to cause a subsequent physiological effect.

[0033] In another embodiment of the methods of the present invention, the
elongated member comprises at least one angle that matches an angle of
said organism's small intestine. In another embodiment of the methods of
the present invention, the elongated member further comprises an angle of
about 70°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
70°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
71°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
72°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
73°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
74°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
75°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
76°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
77°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
78°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
79°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
80°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
81°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
82°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
83°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
84°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
85°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
86°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
87°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
88°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
89°. In another embodiment of the methods of the present
invention, the elongated member further comprises an angle of about
90°. In another embodiment of the methods of the present
invention, the elongated member comprises two angles, each matching an
angle of said organism's small intestine.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1 is a general thawing of the stomach and duodenum of the
small intestine.

[0035] FIG. 2 depicts several exemplary mechanisms through which satiety
signals may be generated.

[0036] FIG. 3 is a perspective view of one embodiment of a duodenal/small
intestinal insert in accordance with the present invention positioned
inside the stomach and small intestine.

[0039] FIG. 6 is a perspective view of an alternative embodiment showing
an elongated member and illustrating attached flow reduction elements.

[0040] FIG. 7 is a perspective section view of a central tube and an
anchoring member.

[0041] FIG. 8 is a perspective view of an alternative embodiment of a
central tube and an anchoring member.

[0042] FIG. 9 is a section view of a central tube of the present invention
that can lodge in the small intestine for a period of time without any
anchoring to the stomach or pylorus.

[0043] FIG. 10 illustrates a central tube attached to an expandable
sleeve, the expandable sleeve allowing expansion of particular segments
of the central tube to form flow reduction elements.

[0044] FIG. 11 illustrates an expandable sleeve in a collapsed
configuration for insertion into the small intestine.

[0045] FIG. 12 illustrates one mechanism for keeping flow reduction
elements formed with an expandable sleeve in a desired expanded
configuration.

DETAILED DESCRIPTION

[0046] It is to be understood that the present invention is not limited to
the particular embodiments, materials, and examples described herein, as
these may vary. It is also to be understood that the terminology used
herein is used for the purpose of describing particular embodiments only,
and is not intended to limit the scope of the present invention. It must
be noted that as used herein and in the appended claims, the singular
forms "a," "an," and "the" include the plural reference unless the
context clearly dictates otherwise. Thus, for example, a reference to "a
flow reduction element" or "a satiety signal" is a reference to one or
more flow reduction elements or satiety signals and includes equivalents
thereof known to those skilled in the art and so forth.

[0047] Unless defined otherwise, all technical terms used herein have the
same meanings as commonly understood by one of ordinary skill in the art
to which this invention belongs. Specific methods, devices, and materials
are described, although any methods and materials similar or equivalent
to those described herein can be used in the practice or testing of the
present invention.

[0048] The phrases "satiety signal(s)" and "signal(s) of satiety" include
any biological occurrence that contributes to a feeling of fullness
and/or the cessation, slowing or reduction of food intake. Generally,
satiety signals are initiated or begin through vagal afferent nerve
signals and/or through the arrival at the brain of hormones or other
molecules that are released (either directly or indirectly) in response
to digestive occurrences. When these vagal afferent nerve signals and/or
hormones or other molecules arrive at the brain, they can trigger
numerous different neural pathways that contribute to a feeling of
fullness and/or the cessation, slowing or reduction of food intake. The
phrases "satiety signal(s)" and "signal(s) of satiety" are meant to
include both the origination of these signals in the periphery and their
integration within the central nervous system which can ultimately affect
behavior.

[0049] The phrase "activate a receptor" includes that a molecule comes
into close enough contact with a receptor to induce a physiological
change in the receptor or that an event such as mechanical deformation or
stretch induces a physiological change in a receptor.

[0050] The phrase "activate a receptor . . . to cause a physiological
effect" includes that a molecule has come into close enough contact with
a receptor to induce a physiological change in the receptor or that an
event such as mechanical deformation or stretch induces a physiological
change in a receptor such that one of a number of physiological events
occurs. For example, the change can cause an effect such as the release
of a molecule from the receptor's cell, the opening or closing of an ion
channel or an increase or decrease in the activity of a g-protein, kinase
or cellular enzyme. The effect can be an increase or a decrease in the
transcription of a gene. The effect can also be to make another
physiological effect more or less likely to occur given the existence of
other physiological events. For example, the effect can be to make the
opening or closing of an ion channel more or less likely based on the
reactivation of the same receptor or the activation of a different
receptor. The effect also can be the firing of an afferent nerve fiber or
the making of the firing of an afferent nerve fiber more or less likely.
All of these physiological effects can either serve to create satiety
signals or can lead to additional downstream effects, such as protein
formation and/or release that can serve to create satiety signals.

[0051] The term "bioactive material(s)" refers to any organic, inorganic,
or living agent that is biologically active or relevant. For example, a
bioactive material can be a protein, a polypeptide, a polysaccharide
(e.g. heparin), an oligosaccharide, a mono- or disaccharide, an organic
compound, an organometallic compound, or an inorganic compound, an
antimicrobial agent (including antibacterial and anti-fungal agents),
anti-viral agents, anti-tumor agents, immunogenic agents and lipids. It
can include a living or senescent cell, bacterium, virus, or part
thereof. It can include a biologically active molecule such as a hormone,
a growth factor, a growth factor-producing virus, a growth factor
inhibitor, a growth factor receptor, an anti-inflammatory agent, an
antimetabolite, an integrin blocker, or a complete or partial functional
insense or antisense gene. It can also include a man-made particle or
material, which carries a biologically relevant or active material. An
example is a nanoparticle comprising a core with a drug and a coating on
the core. A bioactive material also can be a by-product of digestion or
an agent that alters the pH of its surrounding environment.

[0052] Bioactive materials also can include drugs such as chemical or
biological compounds that can have a therapeutic effect on a biological
organism. Bioactive materials include those that are especially useful
for long-term therapy such as hormonal treatment. Examples include drugs
for suppressing appetite, contraception and hormone replacement therapy,
and for the treatment of diseases such as osteoporosis, cancer, epilepsy,
Parkinson's disease and pain. Suitable bioactive materials can include,
without limitation, analgesics and analgesic combinations, antiasthmatic
agents, anticonvulsants, antidepressants, antidiabetic agents,
antineoplastics, antipsychotics, and agents used for cardiovascular
diseases such as anti-coagulant compounds.

[0053] Bioactive materials also can include precursor materials that
exhibit the relevant biological activity after being metabolized,
broken-down (e.g. cleaving molecular components), or otherwise processed
and modified within the body. These can include such precursor materials
that might otherwise be considered relatively biologically inert or
otherwise not effective for a particular result related to the medical
condition to be treated prior to such modification.

[0054] Combinations, blends, or other preparations of any of the foregoing
examples can be made and still be considered bioactive materials within
the intended meaning herein. Aspects of the present invention directed
toward bioactive materials can include any or all of the foregoing
examples.

[0056] Bioactive materials of the present invention also can include,
without limitation, naturally-occurring or synthesized hormones.
Non-limiting examples of such hormones include corticosteroids including
mineralocorticosteroids (including, without limitation cortisol,
deoxycorticosterone and fluorohydrocortisone) and glucocorticoids
(including beclomethasone, betamethasone, cortisone, dexamethasone,
fluocinolone, fluocinonide, fluocortolone, fluorometholone,
fluprednisolone, flurandrenolide, halcinonide, hydrocortisone, medrysone,
methylprednisolone, paramethasone, prednisolone, prednisone and
triamcinolone (acetonide)). Androgenic steroids, such as without
limitation, danazole, fluoxymesterone, mesterolone, methyltestosterone,
testosterone and salts thereof can also be included. Anabolic steroids,
such as without limitation, calusterone, nandrolone and salts thereof,
dromostanolone, oxandrolone, ethylestrenol, oxymetholone, methandriol,
stanozolol methandrostenolone, testolactone can also can be included.
Antiandrogen steroids, such as without limitation, cyproterone acetate
can also be included. Estrogens including diethylstilbestrol, estradiol,
estriol, ethinylestradiol, mestranol, and quinestrol as well as
anti-estrogens, such as chlorotrianisene, clomiphene, ethamoxytriphetol,
nafoxidine, tamoxifen can be included.

[0094] FIG. 1 shows the human stomach 4 and duodenum of the small
intestine 10. Important features are the esophagus 2, stomach 4, antrum
7, pylorus 8, pyloric valve 11, duodenum 10, jejunum 12 and ampulla of
Vater 13. Functionally, the esophagus 2 begins at the nose or mouth at
its superior end and ends at the stomach 4 at its inferior end. The
stomach 4 encloses a chamber which is characterized, in part, by the
esophageal-gastric juncture 6 (an opening for the esophagus 2) and the
antrum-pyloric juncture 5 (a passageway between the antrum 7 through the
pylorus 8 to the duodenum 10 of the small intestine). The pylorus 8
controls the discharge of contents of the stomach 4 through a sphincter
muscle, the pyloric valve 11, which allows the pylorus 8 to open wide
enough to pass sufficiently-digested stomach contents (i.e., objects of
about one cubic centimeter or less). These gastric contents, after
passing into the duodenum 10, continue into the jejunum 12 and on into
the ileum (not shown). The duodenum 10, jejunum 12 and ileum make up what
is known as the small intestine. However these individual portions of the
alimentary canal are sometimes individually referred to as the small
intestine. In the context of this invention the small intestine can refer
to all or part of the duodenum, jejunum and/or ileum. The ampulla of
Vater 13, which provides bile and pancreatic fluids that aid in digestion
is shown as a small protrusion on the medial wall of the duodenum 10.

[0095] The adult duodenum, described as having four parts, is about 20-25
cm long and is the shortest, widest, and most predictably placed part of
the small intestine. The duodenum forms an elongated `C` that lies
between the level of the first and third lumbar vertebrae in the supine
position. Susan Standring (ed.), GRAY's ANATOMY, 39th Ed., 1163-64
(2005).

[0096] The first part of the duodenum, often referred to as the duodenal
bulb 460, is about 5 cm long and starts as a continuation of the duodenal
end of the pylorus 8. This first part of the duodenum passes superiorly,
posteriorly and laterally for 5 cm before curving sharply inferiorly into
the superior duodenal flexure 465, which marks the end of the first part
of the duodenum. Id. The second part of the duodenum, often called the
vertical duodenum 470, is about 8-10 cm long. It starts at the superior
duodenal flexure 465 and runs inferiorly in a gentle curve towards the
third lumbar vertebral body. Here, it turns sharply medially into the
inferior duodenal flexure 475 which marks its junction with the third
part of the duodenum. Id. The third part of the duodenum, often called
the horizontal duodenum 480, starts at the inferior duodenal flexure and
is about 10 cm long. It runs from the right side of the lower border of
the third lumbar vertebra, angled slightly superiorly, across to the left
and ends in continuity with the fourth part of the duodenum in front of
the abdominal aorta. Id. The fourth part of the duodenum is about 2.5 cm
long. It starts just to the left of the aorta and runs superiorly and
laterally to the level of the upper border of the second lumbar vertebra.
It then turns antero-inferiorly at the duodenojejunal flexure and is
continuous with the jejunum. Id. Some embodiments of the present
invention take advantage of this predictable configuration of the small
intestine to provide duodenal/small intestinal implants that do not
require anchoring within the pylorus or stomach (described more fully
infra).

[0097] The digestive process starts when consumed foods are mixed with
saliva and enzymes in the mouth. Once food is swallowed, digestion
continues in the esophagus and in the stomach, where the food is combined
with acids and additional enzymes to liquefy it. The food resides in the
stomach for a time and then passes into the duodenum of the small
intestine to be intermixed with bile and pancreatic juice. Mixture of the
consumed food with bile and pancreatic juice makes the nutrients
contained therein available for absorption by the villi and microvilli of
the small intestine and by other absorptive organs of the body.

[0098] The presence of partially digested food within the stomach and
small intestine begins a cascade of biological signals that create
satiety signals and contribute to the cessation of food intake. One such
satiety signal is initiated by the release of cholecystokinin ("CCK").
Cells of the small intestine release CCK in response to the presence of
digested foods, and in particular, without limitation, in response to
dietary fat, fatty acids, small peptides released during protein
digestion and amino acids. Wynne et al., 184 J. ENDOCRIN. 291-318 (2005);
Havel, 226 SOC'Y FOR EXP. BIOL. AND MED. 963-977 (2001). Once released in
response to these dietary signals, CCK remains elevated for about 5
hours. Liddle et al., 75 J. CLIN. INV. 1144-1152 (1985). Elevated levels
of CCK reduce meal size and duration and may do so through a number of
different mechanisms. Gibbs et al., 84 J. COMP. PHYSIOL. AND PSYCH.
488-95 (1973); Kissileff et al., 285 AM. J. OF PHYSIOL--REG., INT. AND
COMP. PHYSIOL. R992-98 (2003). For example, CCK may act on CCK-A
receptors in the liver and within the central nervous system to induce
satiety signals. CCK stimulates vagal afferent fibers in both the liver
and the pylorus that project to the nucleus tractus solitarius (NTS), an
area of the brain that communicates with the hypothalamus to centrally
regulate food intake and feeding behavior. CCK also stimulates the
release of enzymes from the pancreas and gall bladder and inhibits
gastric emptying. Liddle et al., supra; Moran & Schwarz, 9 CRIT. REV. 1N
NEUROBIOL. 1-28 (1994). Because CCK is a potent inhibitor of gastric
emptying, some of its effects on limiting food intake may be mediated by
the retention of food in the stomach. Wynne et al., supra; Havel, supra.

[0100] Pancreatic peptide (PP) is released in proportion to the number of
calories ingested. Circulating levels of PP also have been shown to be
increased by gastric distension. Elevated levels of PP have been shown to
reduce food intake and body weight. Malaisse-Lagae et al., 33 EXPERIENTIA
915-17 (1977); Asakawa et al., 124 GASTROENTEROL. 1325-36 (2003). Humans
given an infusion of PP demonstrate decreased appetite and an about 25%
reduction in food intake for about 24 hours following the infusion.
Batterham et al., 88 J. CLIN. ENDOCRINOL. AND METAB. 3989-92 (2003). PP
may exert some of its anorectic effects via vagal afferent pathways to
the brainstem. Asakawa et al., supra. PP also may reduce food intake
through its suppression of gastric ghrelin mRNA expression.

[0101] Peptide YY3-36 (PYY3-36) is another biological signal
whose peripheral release may be correlated with reduced food intake
and/or the cessation of eating. Specifically, low levels of PYY3-36
have been correlated with obesity while its administration decreases
caloric intake and subjective hunger scores. Batterham et al., supra.
Indeed, intravenous (i.v.) administration of PYY3-36 can reduce food
intake by about 30% for up to about 12 hours. Batterham et al., 349 NEW
ENGLAND J. MED. 941-48 (2003); Batterham et al., 418 NATURE 650-54
(2002). PYY3-36 may reduce food intake through its effects of
suppressing ghrelin expression, delaying gastric emptying, delaying
various secretion from the pancreas and stomach and increasing the
absorption of fluids and electrolytes from the ileum after a meal.

[0102] Insulin and leptin are two additional biological signals that
regulate satiety and eating behavior. Through parasympathetic
innervation, β cells of the endocrine pancreas release insulin in
response to circulating nutrients such as, without limitation, glucose
and amino acids, and in response to the presence of GLP-1 and gastric
inhibitory peptide (GIP). Havel, supra. Insulin stimulates leptin
production from adipose tissue via increased glucose metabolism.

[0106] In relation to the present invention, if the passage of partially
digested food as described is partially blocked within the duodenum of
the small intestine and the flow rate through this area is reduced, the
emptying of the stomach and the duodenum will occur more slowly. This
slowing, by itself, may create extended feelings of satiety and thus lead
to a decrease in food intake (due to the retention of food in the stomach
for a longer period of time). The slowing of the passage of food also
provides a greater amount of time for the partially digested food to
interact with chemoreceptors, stretch receptors and mechanoreceptors
along the GI tract so that stimulation of satiety signals may be
increased and/or prolonged. For example, increased and/or prolonged
satiety signals may lead to a reduction in food intake by leading to a
shorter duration of food intake and/or longer periods between food
intake.

[0107] In addition to keeping partially-digested food within the small
intestine for an extended period of time, the methods and devices of the
present invention also can enhance and/or prolong the release and/or
occurrence of satiety signals by releasing signals into the small
intestine themselves. For example, in one embodiment, the methods and
devices of the present invention can release nutrient products of
digestion to stimulate chemoreceptors to cause the release of hormones
and/or other molecular signals that contribute to the creation of satiety
signals. In another embodiment, the methods and devices of the present
invention may exert a small amount of pressure on the walls of the GI
tract to stimulate stretch and/or mechanoreceptors to generate and send
satiety signals to the brain. In another embodiment, the methods and
devices of the present invention can release signals, such as, without
limitation nutrient by-products of digestion of food, to stimulate
chemoreceptors as described above and can exert a small amount of
pressure on the walls of the small intestine as described above to
contribute to the generation of satiety signals.

[0108] The methods and devices of the present invention may also
contribute to weight loss and the treatment of obesity by covering
portions of the walls of the small intestine, thus blocking some nutrient
uptake and/or interrupting or reducing the intermixing of the digestive
fluids. In one embodiment, the methods and devices of the present
invention may further include a central tube which funnels a portion of
the consumed food through the small intestine without being fully
digested or absorbed. In these manners, the methods and devices of the
present invention can inhibit the absorption of partially digested food
materials. The partially digested food materials are then passed to the
large intestine for elimination with limited caloric absorption by the
body.

[0109] FIG. 2 depicts several exemplary non-limiting mechanisms through
which satiety signals may be generated. In this FIG. 2, a by-product of
digestion, such as a fatty acid or other protein, stimulates an L-cell of
the small intestine to release CCK locally and into the circulation. CCK
released locally can stimulate vagal afferent nerve fibers in the area to
generate satiety signals to the central nervous system (CNS). CCK that
enters the circulation can travel to the liver to, without limitation,
stimulate vagal afferent nerve fibers in the liver to generate satiety
signals to the CNS. CCK in the circulation can travel to the gall bladder
and pancreas to upregulate the digestion-related activities of these
organs. CCK in the circulation also can travel to the CNS itself to
contribute to the creation of a satiety signal. Once satiety signals are
received and integrated within the CNS, the CNS can trigger physiological
effects that serve to contribute to a feeling of fullness and/or the
cessation, slowing or reduction of food intake.

[0110] FIG. 3 shows one exemplary non-limiting small intestinal insert 20
made in accordance with the present invention that can contribute to the
creation of satiety signals. The insert 20 is positioned in the stomach 4
and small intestine 10. The insert 20 has a proximal portion 30 and a
distal portion 40, and a central tube 50 that extends from the proximal
portion 30 to the distal portion 40. One or more flow reduction elements
200 that are sized to fit within the small intestine 10 can be attached
to the central tube 50. While not required, the portion of the central
tube 50 near the ampulla of Vater 13 generally will not include a flow
reduction element 200 so that the introduction of bile and pancreatic
fluid into the small intestine is not impeded.

[0111] In one embodiment, the central tube 50 has an anchoring member 100
near its proximal end 52, with the anchoring member 100 securing the
proximal end 52 of the central tube 50 in the antrum 7 of the stomach.
The anchoring member 100 is sized so that it will not pass through the
pylorus 8. In this way, embodiments of the present invention including an
anchoring member anchor the flow reduction elements 200 within the small
intestine. In one embodiment, the anchoring member can be established by
one or more inflatable balloons 102 that when inflated are larger than
the pylorus 8. The inflatable balloons 102 can be deflated for delivery
into the stomach and then inflated inside the stomach. The inflatable
balloons 102 can also be deflated for later removal using endoscopic
techniques.

[0112] The length of the central tube 50 can be established depending on
the therapeutic result desired. For example, the central tube 50 and the
one or more attached flow reduction elements 200 may extend into a
portion of or through the entire duodenum 10. On some patients the
central tube 50 and the one or more attached flow reduction elements 200
may extend past the duodenum 10 and into the jejunum 12. It is
anticipated that differing lengths of central tubes and differing numbers
and configurations of the flow reduction elements can be used by a
physician to treat various body types and metabolic demands. In one
example, if a patient is 20% overweight, a physician might select a
length of central tube 50 with attached flow reduction elements 200 that
permit absorption of only 80% of the nutritional potential of a typical
daily intake of calories. This reduction of caloric intake over time
could lead to an appropriate amount of weight loss in the patient.

[0113] FIG. 4 shows one embodiment of a central tube 50 with an outer wall
54 and an inner wall 56 that define an interior space 58. The interior
space 58 forms an inner lumen 59 that may be continuous from the proximal
end 52 of the central tube 50 to just short of the distal end 53 of the
central tube 50. The distal end 53 of the central tube 50 is sealed at a
point 55 so that fluid introduced into the central tube 50 does not leak
out distally into the small intestine. In some embodiments a valve 90 can
be located substantially at the proximal end of the inner lumen 59. The
valve 90 may be a self sealing valve that has a septum 92 that can be
accessed by a needle or blunt tip tube for introduction of fluid into the
inner lumen 59. The valve 90 also can be accessed so that the fluid
inside the inner lumen 59 of the central tube 50 can be aspirated for
removal. It is to be understood that the valve type is not limited to a
septum type valve only, and that other types of mechanical valves may
also be used in place of the septum valve described. Particular
embodiments of the present invention are adapted to accept fluids in this
manner so that the devices of the present invention can be implanted in a
deflated configuration and later expanded into an inflated configuration.

[0114] As shown in FIG. 4 and as mentioned above, one or more flow
reduction elements 200 can be attached to the central tube 50. In some
embodiments the diameter of each flow reduction element 200 can be
concentric with the axis of the central tube 50. In the embodiment
depicted in FIG. 4, each flow reduction element 200 has an outer wall
210, an inner wall 212, and an inner space 214. At or near its
proximally-oriented surface 220 and also at or near its distally-oriented
surface 222, each flow reduction element 200 can be attached to the
central tube 50 with the inner space 214 of the flow reduction element
200 in fluid communication with the lumen 59 of the central tube 50, such
that the inner space 214 surrounds the outer wall 54 of the central tube
50. Each flow reduction element 200 may be attached to the central tube
50 by, without limitation, adhesives, heat bonding, mechanical restraint
or other suitable methods.

[0115] As also depicted in FIG. 4, the central tube 50 can be formed with
plural inlet/exit ports 216 that are located inside respective flow
reduction elements 200. More specifically, each port 216 is formed
completely through the central tube wall 51 to establish a pathway for
fluid communication between the inner lumen 59 of the central tube 50 and
the inner space 214 of the respective flow reduction elements 200.
Consequently, the inner lumen 59 of the central tube 50 may be used to
introduce fluid into the inner spaces 214 of the flow reduction elements
200 and to inflate the flow reduction elements 200 from a collapsed
configuration, in which insertion and removal of the flow reduction
elements 200 is facilitated, to an inflated configuration shown in FIG.
4, in which resistance to food passage is increased to induce satiety.
Thus, as suggested earlier, the flow reduction element or elements 200 in
this embodiment act as balloons that can be deflated and collapsed around
the central tube 50 for introduction into the small intestine and then
inflated to the desired diameter once in position.

[0116] In one embodiment, individual flow reduction elements 200 of the
present invention can be elastic balloons or inelastic balloons. When an
elastic balloon material is used to establish a flow reduction element
200, the flow reduction element 200 inflates to a diameter that is
dependent on the volume of fluid introduced into the inner space of the
flow reduction element. This embodiment permits adjustment of the balloon
size as determined by the physician. If the balloon is too small, for
instance, additional fluid could be introduced to enlarge the balloon
diameter. Alternatively, if the balloon is too large, additional fluid
could be removed to shrink the balloon diameter. It is understood that an
alternate embodiment consisting of an inelastic balloon that inflates to
a diameter that is independent of a volume of fluid introduced into its
inner space is also included within the present invention. The diameter
of this type of balloon is fixed when manufactured and does not permit in
situ adjustment of the balloon size. However, this type of balloon
prevents possible over inflation and rupture if too much fluid is
introduced into the balloon.

[0117] The flow reduction elements 200 shown in FIG. 4 have the shape of a
round sphere. However, other shapes are contemplated and any shape that
effectively functions to inhibit the passage of partially digested food
in the small intestine is acceptable in accordance with the present
invention. It is understood that the ability of the small intestinal
insert to remain within the small intestine can be affected by the shape,
orientation and tautness of the flow reduction elements 200. For example
alternate shapes such as ovoid, elliptical, elongated ellipse and even
irregular non-geometrical shapes could be used in accordance with the
present invention.

[0118] FIG. 5 illustrates an alternative embodiment of the present
invention in which one or more flow reduction elements 300 are
eccentrically attached to a central tube 350. In this embodiment the axis
or diameter of the flow reduction element or elements 300 is not
concentric with the axis of the central tube. The outer wall 302 of the
flow reduction element is attached to the side of an outer wall 354 of
the central tube 350. An inner space 314 of each flow reduction element
300 is eccentric relative to the axis of the central tube 350 and is in
fluid communication with an inner lumen 359 of the central tube 350
through a respective opening 316. As was the case with the embodiment
shown in FIG. 4, in the embodiment shown in FIG. 5 the inner lumen 359
can be used to introduce and remove fluid into the inner space 314 of the
flow reduction element 300 to move the flow reduction element 300 between
inflated and deflated configurations.

[0119] In one embodiment of the present invention, the flow reduction
elements 300 can be inflated with a fluid, including a liquid and/or a
gas. In one embodiment, the gas can be, without limitation, air, nitrogen
or carbon dioxide. In another embodiment a liquid can be, without
limitation, water or water mixed with other solutions. Any appropriate
inflation medium can be modified to deliver bioactive materials or other
signals that can diffuse from the insert of the present invention into
the small intestine to trigger biological signals of satiety. When
bioactive materials are delivered through an inflation medium, the
central tube and/or flow reduction elements should be permeable to the
bioactive materials. Porosity can be adjusted to control the diffusion
rate of the bioactive materials.

[0120] When inflating the flow reduction elements of the present
invention, it can be important for the physician to monitor the flow
reduction element 300 location in the small intestine and the diameter of
the flow reduction element relative to the diameter of the small
intestine. For this purpose, the flow reduction element can be inflated
with a radiopaque fluid that is visible on X-ray. When the flow reduction
element contains radiopaque fluid, a physician can non-invasively
visualize the size and placement of the flow reduction element(s) from
outside the patient's body. This knowledge enables the physician to
adjust the size and/or placement of the flow reduction element(s).
Likewise radiopaque marker bands 218 as shown in FIG. 5 can be placed
around the central tube to facilitate visualization of the central tube's
location in the small intestine. The radiopaque marker bands 218 can be
placed at predetermined intervals so that the distance inside the small
intestine can be used as depth markers and can be measured from outside
of the body.

[0121] The central tube and flow reduction elements of the present
invention can be flexible. In one embodiment, they can be constructed of
a polymeric material that can be easily formed or extruded and delivered
with the aid of an endoscope by known techniques. A central tube 50 that
is soft and flexible will contour to the anatomy of the gastrointestinal
tract and provide less irritation of the stomach and intestinal lining.

[0122] FIG. 6 shows an alternative embodiment of the present invention
with a central shaft 450 around which flow reduction elements are
concentrically attached 400 and/or are eccentrically attached 410. The
elements 400, 410 can be attached to the central shaft 450 by, without
limitation, heat fusing, adhesives or other suitable methods as known in
the art. These flow reduction elements 400 can be made from material that
can be folded or collapsed to a first volume suitable for insertion with
the aid of an endoscope and then can self expand to a second volume
suitable for restricting the flow of partially digested food according to
the present invention. These flow reduction elements can be made from
materials such as, without limitation, sponge, foam, hydrogels or springs
that can be compacted into a small volume and then self expand to a
pre-determined shape and volume when unrestricted. These flow reduction
elements may also be impregnated with bioactive materials or other
signals that can trigger biological signals of satiety. The central shaft
450 of the embodiment depicted in FIG. 6 can be solid and without an
inner lumen or inner space. In another embodiment the central shaft 450
may include a passageway for consumed food so that the food can pass
through the small intestine without being fully absorbed. Because the
flow reduction elements self expand, the need for an inflation system is
eliminated and this embodiment represents a simple mechanical design.

[0123] Turning to various anchoring members that can be used in accordance
with the present invention, FIG. 7 depicts one such member. In FIG. 7,
the central tube 50 has an anchoring member 100 near its proximal end 52.
As stated earlier, the anchoring member 100 can be established by one or
more inflatable balloons 102. These balloons 102 can be eccentrically
attached to the central tube at point 104 near the proximal end 52 of the
central tube 50. These balloons can be formed in many shapes and are not
limited to the spherical shape shown. The central tube can be formed with
an opening 116 for each respective balloon 102 so that a pathway for
fluid communication is established between the inner lumen 59 of the
central tube 50 and the inner space of each balloon 106. The inner lumen
59 is used to introduce fluid into the inner space of the balloon 106 and
inflate the balloon 102 from a first volume in a collapsed state to a
second volume or inflated state.

[0124] When the one or more balloons 102 of the anchoring member 100 are
fully inflated, they secure the proximal end of the central tube 52
within the antrum of the stomach. The one or more inflatable balloons 102
have a combined cross sectional diameter greater than the diameter of the
pyloric valve to prevent migration across the pylorus. The inflatable
balloons 102 can be inflated and deflated by adding or removing fluid
from the central tube inner lumen 59. The inflatable balloons 102 may be
connected to the same central tube inner lumen 59 as the one or more flow
reduction elements attached to the central tube and can be inflated
simultaneously with the flow reduction elements. The central tube 50 may
also have more than one inner lumen so that the inflatable balloons 102
and individual one or more flow reduction elements can be inflated and
deflated independently as well.

[0125] FIG. 8 illustrates another embodiment of an anchoring member 100 of
the present invention deployed in the antrum 7. In this embodiment, a
central tube 50 is attached to an inverted umbrella skeleton 160. This
skeleton 160 has a ring 162 that surrounds the central tube 50 and is
supported by struts. In the depicted embodiment the ring 162 is supported
by 3 struts 164, 165 and 166, however more or fewer struts can be
successfully employed. In the embodiment depicted in FIG. 8, the struts
are joined together at the central tube 50 at point 167 and attached to
the ring 162 at points 170, 171 and 172. The ring 162 of this anchor
configuration can be made from, without limitation, flexible plastic
material or flexible wire and has a diameter significantly larger than
the diameter of the pyloric valve. This umbrella skeleton 160 can be
collapsed around the central tube 50 for insertion into the stomach with
the aid of an endoscope. As the device is released from the endoscope,
the umbrella skeleton 160 can spring out and assume a configuration
similar to that shown in FIG. 8. The struts 164, 165 and 166 may be made
from, without limitation, plastic, metal or from plastic covered metal.
The edge of the ring which is in contact with the antrum walls 163, may
be constructed to assist in securing the umbrella ring 162 to the walls
of the antrum. In one embodiment, the surface may be roughened to
increase surface friction or the wall may have protrusions or barbs that
physically attach to the stomach lining.

[0126] FIG. 9 shows a central tube 50 of the present invention that may
lodge and remain in the small intestine for a period of time without any
anchoring to the stomach or pylorus. Embodiments of the present invention
that can lodge and remain within the small intestine for a period of time
without any anchoring to the stomach or pylorus do so by (i) adopting a
central tube with appropriately placed angles that mimic the contours of
the small intestine; and (ii) flow reduction elements of an appropriate
diameter that help to hold the intestinal insert in place. In one
embodiment, while not required, these flow reduction elements can have an
abrasive surface or anchoring barbs that can help them adhere to the
walls of the small intestine.

[0127] In FIG. 9, the first three parts of the duodenum, including the
duodenal bulb 10A, the vertical duodenum 10B, and the horizontal duodenum
10C are depicted. The flow reduction elements of the depicted embodiment
have been removed for clarity. Distal to the pylorus 8 and immediately
after entering the duodenum 10, the central tube 50 can assume a sharp
bend of radius β between the duodenal bulb 10A and the vertical
duodenum 10B, and a sharp bend of radius a between the vertical duodenum
10B and horizontal duodenum 10C. In one embodiment the radius β and
the radius a may be between about 45° and about 110°. In
another embodiment the radius β and the radius a may be between
about 60° and about 100° such that the central tube 50
bends to follow the inner lumen of the duodenum 10 at these locations
that contain predictably configured bends. In another embodiment the
radius β and the radius a may be about 80°. While most
embodiments of the present invention will include lengths that require
adoption of a β and an α angle, shorter devices adopting one
or the other are also included within the scope of the present invention.
In these described embodiments of the present invention, it can be
advantageous that the central tube 50 be flexible enough to conform to
the sharp angulations of the small intestine to avoid kinking. One or
more flow reduction elements with a diameter about equal to that of the
small intestine are also included along the length of the central tube
50. In one embodiment, this diameter is about 3 cm. In another embodiment
this diameter is about 4 cm.

[0128] The central tube 50 can be pre-formed with a configuration that
conforms to the duodenal angulations prior to insertion in the body. This
embodiment of the present invention can be constrained in a straight
configuration by a stiffening rod 110 placed down the inner lumen 59 of
the central tube 50 as shown. This stiffening rod 110 can be placed into
a separate lumen designed to house this stiffening rod or can be imbedded
in the wall of the central tube 50. Upon insertion into the patient with
the aid of an endoscope, when the central tube 50 reaches the location of
the sharp bends in the duodenum 10, the stiffening rod 110 can be
withdrawn, thereby allowing the central tube 50 to assume a pre-formed
shape. In another embodiment, the central tube 50 may have a shape memory
alloy wire embedded inside the central tube wall 51 or residing in the
inner lumen 59. This shape memory alloy wire has a pre-set bend
configuration with a radius β and a radius a that matches the bend
configuration of the duodenum and is positioned in the central tube 50 at
the corresponding location. Upon insertion into the patient with the aid
of an endoscope, when the central tube 50 reaches the location of the
sharp bend in the duodenum 10 and the shape memory alloy wire reaches a
pre-set transition temperature equal to body temperature or about
37° C., the wire assumes the programmed shape and forces the
central tube 50 and the central tube wall 51 to assume the same shape. In
another embodiment, the central tube 50 may have a spring embedded inside
the central tube wall 51 or inner lumen 59. This spring could be
pre-shaped to the anatomy of the wall of the small intestine. The spring
is held straight during delivery and conforms to the small intestine
anatomy after release. The shape enables the device to remain in place.
In one embodiment, due to its configuration that matches the predictable
placement and configuration of the small intestine, the device can remain
in place for a period of time within the small intestine without
anchoring to the stomach or pylorus of the stomach. While the present
embodiments of the present invention can remain in the small intestine
for a period of time without anchoring to the stomach or pylorus, they
are not intended to remain indefinitely. In one embodiment, the inserts
are endoscopically removed after a predetermined period of time. In
another embodiment, the inserts can be formed of a biodegradable material
that is eventually degraded and eliminated from the body.

[0129] FIG. 10 illustrates an embodiment of the present invention where
flow reduction elements can be created through the expansion of portions
of an expandable sleeve. In the embodiment depicted in FIG. 10, a central
tube 50 is attached to an expandable sleeve 508 at the expandable
sleeve's distal end 510 near the distal portion of a duodenal/small
intestinal insert of the present invention. In a delivery configuration
of the depicted embodiment, the opposite proximal end of the central tube
50 is attached to a detachable extension tube 520 that can lock onto a
proximal portion of the central tube 50 when the flow reduction elements
530 are expanded (post delivery). One non-limiting method of detachable
attachment is the use of one or more screws 504, whereby the extension
tube 520 screws into the central tube 50. The central tube 50 may be
pre-formed to have a configuration that conforms to the anatomy of the
duodenum 10 shown in FIG. 1. A central tube 50 so described would force
the expandable sleeve 508 to assume the configuration of the central tube
50. The central tube 50 may be constructed of, without limitation, wire,
spring, superelastic or shape memory alloys, hollow steel tubing or
plastic polymers. In one embodiment a stiffening rod or guide wire 110
can also be inserted through the lumen of central tube 50. The expandable
sleeve 508 may be, without limitation, one or more of a knit, a weave, a
mesh or a braid that can be formed from, without limitation, one or more
of a metal, a wire, a ribbon, a plastic polymer or a biodegradable
material.

[0130] The expandable sleeve 508 herein described is designed to expand at
predefined segments to allow the formation of flow reduction elements
530. In one embodiment, the non-expanded segments 532 of expandable
sleeve 508 may be coated with a polymer to prevent their expansion. In
another embodiment, the flow reduction elements 530 may be covered with a
flexible polymer to prevent partially digested food from entering the
flow reduction elements 530. In another embodiment, a stiffening rod or
guide wire 110 can be inserted through the lumen of central tube 50 to
straighten the central tube 50 when the device is delivered into the
duodenum.

[0131] FIG. 11 illustrates the expandable sleeve 508 consisting of flow
reduction elements 530 in a collapsed configuration for insertion into
the small intestine. In this configuration a force A is applied to the
expandable sleeve 508 to collapse the flow reduction elements 530. The
collapsed form can be restrained by a constraining mechanism such as,
without limitation, a sheath or a tightly wound string, or by applying
sustained traction on the proximal end of the expandable sleeve 508. FIG.
11 also shows portions of the central tube that will remain unexpanded
532, a detachable extension tube 520 and a guidewire 110.

[0132] The expansion of the flow reduction elements 530 in the embodiments
depicted in FIGS. 10 and 11 can occur passively or actively. One
non-limiting example of passive expansion can be the removal of a
constraining mechanism to allow the flow reduction elements 530 to expand
to an original expanded state. Another non-limiting mechanism can be to
release traction on the proximal end of an expandable sleeve 508 to allow
the flow reduction elements 530 to expand to an original expanded state.

[0133] The flow reduction elements 530 of the embodiments depicted in
FIGS. 10 and 11 can expand in a distal to proximal fashion, a proximal to
distal fashion or in a central fashion depending on their relative
position in relation to, in one embodiment, motion of the expandable
sleeve 508 and the central tube 50 to one another. For example, if the
proximal end of the flow reduction element lumen is held in the duodenal
bulb and the central tube 50 is pulled back, the distal end of the flow
reduction element lumen can expand first. Expansion in this direction can
be advantageous because the position of the proximal end of the flow
reduction element lumen remains in the duodenal bulb.

[0134] FIG. 12 illustrates one embodiment of the present invention that
can lock the proximal end of the expandable sleeve 508 to the central
tube 50 at a position to keep the flow reduction elements in a desired
expanded configuration. Traction on the extension tube 520 retracts
central tube 50 until wedge 52 engages the proximal end of the expandable
sleeve 508. The central tube 50 may have multiple ratchet-like wedges
that can lock the expandable sleeve 508 at different degrees of
expansion. The extension tube can be unscrewed from the central tube 50
after deployment of the device and expansion of the expandable sleeve
508.

[0135] As previously stated, in one embodiment, the central tube and/or
flow reduction elements of the present invention can be adapted to
release bioactive materials or other signals that trigger biological
satiety signals. In one embodiment, the one or more of the flow reduction
elements and/or central tube may be a porous and malleable solid designed
to release a signal into the GI tract over time. In one embodiment,
nutrient products of digestion are released from the one or more flow
reduction elements and/or central tube to trigger chemoreceptors within
the GI tract to release molecular signals involved in transmitting and/or
creating satiety signals.

[0136] In addition to delivering bioactive materials to the small
intestine that can reduce food intake, the methods and devices of the
present invention can be used to deliver other bioactive materials
normally taken orally as well. The release of bioactive materials
directly into the small intestine can be advantageous because many
bioactive materials, including many drugs that are generally taken
orally, are degraded by the harsh conditions of the stomach before they
can reach the small intestine to be absorbed. For this reason, many
bioactive materials are coated with layers of protective materials. By
releasing bioactive materials, including drugs, directly into the small
intestine, coatings to protect the bioactive materials are not required.
This lack of required protective coatings can be beneficial for patients
because less unnecessary substances are introduced into their systems. It
also is beneficial to bioactive material and drug manufacturers as a cost
reduction measure.

[0137] The central tube and/or flow reduction elements of the present
invention can have bioactive materials adhered to their surface (through
dip-coating, spray-coating, sputter-coating and a variety of other
techniques known to those of skill in the art) or can be manufactured so
that the materials making up the intestinal insert include and diffuse
such bioactive materials. The central tube and/or flow reduction elements
of the present invention that diffuse bioactive materials, can be created
by a number of different procedures. For example, U.S. Pat. No. 5,019,400
to Gombotz et al., which is hereby incorporated by reference, describes a
low temperature casting process for incorporating proteins into
controlled release polymer matrices. U.S. Pat. No. 6,685,957 to Bezemer
et al., which is hereby incorporated by reference, describes a method to
create a fibrous polymer loaded with bioactive materials that is suitable
for loading bioactive materials such as by-products of digestion. In one
embodiment, the methods described in U.S. Pat. No. 6,685,957 include
synthesizing a polyethylene glycol terephtalate/polybutylene
terephthalate copolymer from a mixture of dimethyl terephthalate,
butanediol (in excess), polyethylene glycol, an antioxidant and a
catalyst. The mixture is placed in a reaction vessel and heated to about
180° C., and methanol is distilled as transesterification
proceeds. During the transesterification, the ester bond with methyl is
replaced with an ester bond with butylene and/or the polyethyene glycol.
After transesterification, the temperature is raised slowly to about
245° C., and a vacuum (finally less than 0.1 mbar) is achieved.
The excess butanediol is distilled off and a prepolymer of butanediol
terephthalate condenses with the polyethylene glycol to form a
polyethylene/polybutylene terephthalate copolymer. A terephthalate moiety
connects the polyethylene glycol units to the polybutylene terephthalate
units of the copolymer and thus such a copolymer also is sometimes
referred to as a polyethylene glycol terephthalate/polybutylene
terephthalate copolymer (PEGT/PBT copolymer).

[0138] When a hydrophobic bioactive material, such as, for example, a
steroid hormone is incorporated by the above-described method, at least
one hydrophobic antioxidant can be present. Hydrophobic antioxidants
which may be employed include, but are not limited to, tocopherols (such
as, without limitation, α-tocopherol, β-tocopherol,
γ-tocopherol, Δ-tocopherol, ε-tocopherol,
ζ1-tocopherol, ζ2-tocopherol, and η-tocopherol)
and 1-ascorbic acid 6-palmitate. Such hydrophobic antioxidants retard the
degradation of the copolymer and retard the release of the bioactive
material. Thus, the use of a hydrophobic or lipophilic antioxidant is
applicable particularly to the formation of loaded polymers which include
bioactive materials which tend to be released quickly, such as, for
example, bioactive materials having a molecular weight less than 500. The
hydrophobic antioxidant(s) may be present in the loaded polymer in an
amount of from about 0.1 wt % to about 10 wt % of the total weight of the
polymer, or from about 0.5 wt % to about 2 wt %.

[0139] When a loaded polymer made according to the above-described
technique includes a hydrophilic bioactive material, the loaded polymer
may also include, in addition to a hydrophobic antioxidant, a hydrophobic
molecule such as, without limitation, cholesterol, ergosterol,
lithocholic acid, cholic acid, dinosterol, betuline, or oleanolic acid,
which may be employed in order to retard the release rate of the agent
from the copolymer. Such hydrophobic molecules prevent water penetration
into the loaded polymer, but do not compromise the degradability of the
polymer matrix. In addition, such molecules have melting points from
about 150° C. to about 200° C. and/or decrease the polymer
matrix diffusion coefficient for the bioactive material to be released.
Thus, such hydrophobic molecules provide for a more sustained release of
a bioactive material from the polymer matrix. The at least one
hydrophobic molecule may be present in the loaded polymer in an amount of
from about 0.1 wt % to about 20 wt %, or from 1.0 wt % to 5.0 wt %.

[0140] U.S. Pat. No. 6,187,330 to Wang et al., which is hereby expressly
incorporated by reference, describes a method of dispersing bioactive
materials, including peptides and proteins, into a polymer by dispersing
the bioactive material in a glassy matrix phase during the melt stage of
the polymer wherein the glass transition temperature is higher than the
melting point of the polymer. The glassy matrix phase described in U.S.
Pat. No. 6,187,330 can be produced by lyophilizing an aqueous solution of
the bioactive material and an appropriate thermoprotectant (such as,
without limitation, trehalose, melezitose, lactose, maltose, cellobiose,
melibiose and raffinose). The particular thermoprotectant selected and
its concentration relative to the bioactive material determines the
precise glass transition temperature of the lyophile. Generally, the
weight ratio of thermoprotectant to bioactive material is between about 2
and 200. One skilled in the art can determine the required glass
transition temperature of any combination. Glass transition is defined as
the reversible change in an amorphous material from (or to) a viscous
rubbery state to (or from) a hard and relatively brittle one (American
Society for Testing and Materials (ASTM) E 1142). Glass transition
temperature (Tg) is defined as the approximate midpoint of the
temperature range at which the glass transition takes place (ASTM D
4092). The glass transition temperature of the glassy matrix phase
containing the peptide bioactive material and the thermoprotectant can be
determined by a variety of techniques, the most popular of which is
differential scanning calorimetry (DSC). If a glassy material is heated
at a constant rate, a baseline shift can be found in the relation of heat
flow and its temperature. The temperature corresponding to the midpoint
of the two baselines is considered the glass transition temperature.

[0141] Lyophilization of the aqueous solution containing the
thermoprotectant, bioactive material and other appropriate excipients, if
any, is carried out using techniques well known in the pharmaceutical
field (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 17th Ed., p.
1538). Lyophilization produces a glassy matrix phase in the form of a
powder or a cake which may be comminuted to produce a powder suitable for
dispersion in the polymer.

[0143] One of skill in the art can determine the amount or concentration
of bioactive material(s) to include on the surface or within the material
of the intestinal inserts of the present invention depending on
particular treatment objectives and desired release profiles. Factors to
consider are described in, for example, U.S. Pat. No. 6,939,557 to Rowe
et al. (which is hereby expressly incorporated by reference) and include
the hydrophobic or hydrophilic nature of the bioactive material(s), the
aggregation and solubility characteristics of the bioactive material(s)
and their particle size; see also REMINGTON: THE SCIENCE AND PRACTICE OF
PHARMACY, 20th ed. Ch. 47, Controlled Release Drug Delivery Systems,
which is hereby expressly incorporated by reference.

[0144] In one embodiment, the intestinal inserts of the present invention,
or portions thereof, can include a topcoat or barrier to slow the
diffusion or release of bioactive materials. Typically, the barrier
should be biocompatible (i.e., its presence does not elicit an adverse
response from the body), and can have a thickness ranging from about 50
angstroms to about 20,000 angstroms. In one embodiment the barrier may
include a polymer provided over the polymer that diffuses bioactive
materials.

[0146] Several methods may be used to deposit a barrier over the inserts
of the present invention. For example, silicide compounds, such as,
without limitation, vanadium disilicide, zirconium disilicide, tungsten
disilicide, titanium disilicide, niobium disilicide, tantalum disilicide,
vanadium silicide, titanium trisilicide, and tantalum trisilicide may be
deposited by sputtering or chemical vapor deposition (CVD). Oxide barrier
coatings, such as, without limitation, tantalum oxide, titanium dioxide,
zirconium oxide, niobium oxide, tungsten oxide, aluminum oxide, and
silicon dioxide can be produced by reactive sputtering. The power source
used in this method may be AC or DC, and utilizes the pure element as a
target with a sputter gas of argon and low levels of oxygen.

[0147] Nitride barrier coatings, such as, without limitation, titanium
nitride, titanium carbonitride, chromium nitride, titanium aluminum
nitride, and zirconium nitride can be deposited on the inserts of the
present invention at relatively low temperatures (i.e., less than
60° C.) by cathodic arc vacuum deposition. Such a method may be
chosen where bioactive materials included within an insert of the present
invention are temperature-sensitive.

[0148] Films of pure metals (without limitation, aluminum, gold, tungsten
and platinum) may be produced by methods such as, without limitation,
physical vapor deposition (PVD), sputtering, thermal evaporation, or
electron beam evaporation. Alloys of these metals can be deposited by
sputtering if, for example, an alloy sputtering target is used or
multiple targets are simultaneously sputtered. Alloys may also be
deposited utilizing thermal evaporation or electron beam evaporation if
several evaporation sources are used simultaneously.

[0149] In one embodiment, it is contemplated that the bather will contain
mostly inorganic material. However, other embodiments can include bathers
with a mixture of organic and inorganic materials or bathers of all
organic materials. Some organic compounds that can be used in accordance
with the present invention include, without limitation,
polyacrylonitrile, polyvinylidene chloride, nylon 6-6, perfluoropolymers,
polyethylene terephthalate, polyethylene 2,6-napthalene dicarboxylate,
and polycarbonate. Generally, the solubility of the drug in the material
of the barrier is less than the solubility of the drug in its polymer
carrier. Also, generally, the diffusivity of the drug in the material of
the bather is lower than the diffusivity of the drug in its polymer
carrier. The bather may or may not be biodegradable.

[0150] Appropriate biodegradable materials that may be used to create a
bather include, without limitation, calcium phosphates such as, without
limitation, hydroxyapatite, carbonated hydroxyapatite, tricalcium
phosphate, beta-tricalcium phosphate, octacalcium phosphate, amorphous
calcium phosphate, and calcium orthophosphate. Certain calcium salts such
as calcium phosphate (plaster of paris) may also be used. The
biodegradability of the bather may act as an additional mechanism for
controlling drug release from the underlying first layer.

[0151] The terms and expressions which have been employed herein are used
as terms of description and not of limitation, and there is no intention
in the use of such terms and expressions of excluding equivalents of the
features shown and described, or portions thereof, it being recognized
that various modifications are possible within the scope of the invention
claimed. Moreover, any one or more features of any embodiment of the
invention can be combined with any one or more other features of any
other embodiment of the invention, without departing from the scope of
the invention.